Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development

Abstract

More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

“…38 The animals with these genetic changes develop invasive intrahepatic cholangiocarcinoma from different precursor lesions, including intraductal papillary neoplasm of the bile duct-like tumors with intestinal and pancreato-biliary epithelium. 38 Among the genes whose changes appear to be less important for the development of intraductal papillary neoplasms of the bile duct due to their infrequency are GNAS, a gene that was found to be linked to the molecular pathogenesis of pancreatic intraductal papillary mucinous neoplasm, [14][15][16] b-catenin, HER2 and EGFR. Activating mutations of GNAS, which codes for a G-protein alphasubunit, were recently discovered in a high number of pancreatic intraductal papillary mucinous neoplasms, few invasive adenocarcinomas associated with intraductal papillary mucinous neoplasm and pancreatic intraepithelial neoplasia lesions and in a small number of intraductal papillary neoplasms of the bile duct.…”

“…[7][8][9][10] In addition, several studies performed on human and transgenic mice revealed a number of genetic changes in key molecular pathways during intraductal papillary mucinous neoplasm development. [11][12][13][14][15][16] In contrast to the more common pancreatic intraductal papillary mucinous neoplasms, intraductal papillary neoplasms of the bile duct have not been well characterized so far, either from the clinical or from the molecular point of view. Most studies of intraductal papillary neoplasms of the bile duct are based on small number of patients, 2,[17][18][19][20][21] and the three largest studies (55-97 patients) [22][23][24] exclusively enrolled Asiatic patients, a considerable proportion of them with hepatolithiasis or Clonorchiasis infection.…”

Clinicopathological significance of somatic RNF43 mutation and aberrant expression of ring finger protein 43 in intraductal papillary mucinous neoplasms of the pancreas

“…GNAS mutations have been found in 40-60% of intraductal papillary mucinous neoplasms, and are known to be exclusive to these tumors among the various pancreatic neoplasms. [4][5][6] Komatsu et al 16 reported that GNAS mutations induced the upregulation of cyclic adenosine monophosphate and overexpression of mucin protein genes in some pancreatic duct-lineage cells; therefore, GNAS mutation appears to play a key role in the secretion of abundant mucin, the most prominent characteristic phenotype of intraductal papillary mucinous neoplasms. Interestingly, the same authors also demonstrated that the exogenous expression of mutated GNAS did not confer a proliferative advantage on pancreatic cancer cells.…”

“…In 2011, it was discovered that intraductal papillary mucinous neoplasms often harbored mutations in GNAS and RNF43. [4][5][6] Most GNAS mutations found in intraductal papillary mucinous neoplasms are either R201H or R201C, which are known to induce gain of function of the encoded protein guanosine nucleotide-binding protein alpha. 7 In contrast, RNF43 mutations are mostly frameshift or nonsense mutations that are expected to induce a lossof-function of the encoded protein ring finger protein 43.…”

Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy

“…Recently genetic mutations in genes such as guanine nucleotide binding protein, alpha stimulating (GNAS), and mutational profiles of targeted next-generation sequencing of cancer genes, have been suggested as an adjunct to cytology and CEA to improve the diagnosis of mucinous cysts and to identify early malignancy within lesions by analyzing cyst fluid 45–47 . These studies are quite promising in substantiating the feasibility of detecting DNA mutations in IPMN using cyst fluid, even when these molecules are at low concentrations, though the performance of these genetic markers needs to be further evaluated in prospective in vivo clinical studies.…”